Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder

Matej Markota,Brandon J Coombes,Miguel L Prieto,Mohit Chauhan,Joanna M Biernacka,Manuel Fuentes,Marin Veldic,Colin L Colby,Alfredo B Cuellar-Barboza,Simon Kung,Beth R Larrabee,Susan L Mcelroy,William V Bobo,David J Bond,Mark A Frye,Teresa A Rummans

doi:10.1038/s41398-018-0242-3

Abstract

Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke’s R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10−13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.

Highlights

Bipolar disorder (BD) is a highly heterogeneous illness, which presents clinical challenges and likely contributes to difficulties in identifying genetic underpinnings of this disorder[1,2,3]
Our results show that SZ-polygenic risk score (PRS) is a better predictor of BD with manic psychosis than of BD with only depressive psychosis or no history of psychosis
This suggests that BD patients with manic psychosis are genetically more similar to SZ than BD patients with a history of only depressive psychosis or BD patients with no occurrence of psychosis

Summary

Introduction

Bipolar disorder (BD) is a highly heterogeneous illness, which presents clinical challenges and likely contributes to difficulties in identifying genetic underpinnings of this disorder[1,2,3]. There is accumulating evidence that these two disorders overlap in neuroimaging, neuropsychological, histological, and clinical features[6,7,8,9,10]. Studies addressing the genetic overlap between BD and SZ have evolved from studying family and twin inheritance to estimating genetic correlation and performing polygenic risk score (PRS) analysis using genome-wide association data from large case–control samples. In a PRS analysis, single-nucleotide polymorphism (SNP) effect sizes from a prior genome-wide association study (GWAS) of “disease A” (e.g., SZ) can be used to calculate the estimated risk of “disease A” for a group of controls and patients with “disease B” (e.g., BD) to evaluate whether on average patients with “disease B” (i.e., BD, in our example) have

Methods

Results

Conclusion